DESCRIPTION: (adapted from the application): Although a number of genes have been identified whose activity changes with age or have otherwise been implicated in aging, it has been difficult to functionally related these genes to the aging process. The recent development of some powerful molecular genetic tools provides the exciting possibility of moving beyond the stage of correlation to directly testing the role of these genes in aging. These tools include the ability to (1) enhance the level of expression of individual genes by the introduction of chimeric gene constructs into transgenic mouse models or (2) completely eliminate the expression of specific genes by gene knock out. However, the interpretation of the results obtained is still limited by the fact that the affected gene is either over- or under-expressed throughout the life span. This problem is particularly acute during prenatal development as the embryo may simply die or alternatively may compensate, sometimes remarkable, for the aberrant expression of the manipulated gene. Therefore, it can be difficult to define the normal contribution of specific genes to complex life-long processes, such as aging, by the application of conventional transgenic mouse or knock out mouse approaches alone. The Developmental Core will utilize the tetracycline (tet) regulatable transcription system to develop a practice means of either "over" or "under" expressing the activity of specific genes only at selected times during the life span of the aging mouse model. This Core has three aims. The first is to develop transgenic mouse models in which the expression of the tet-sensitive transactivator protein (tTA) gene is driven by a promoter that is activated in a broad range of tissues. Aim 2 is to identify the best approach for administering tet to optimally repress the function of tTA in transgenic founder lines prepared in Aim 1. The third aim is to assist the project leaders in the application of these models of regulating gene expression in their individual projects. The completion of these aims may open a new area in the study of aging by substantially enhancing the capacity of transgenic models to more directly test the role of specific genes in aging and the mechanisms by which dietary restriction affects this process.